Regulatory T cells (otherwise known as “Tregs” or Foxp3+ T regulatory cells) are an important component of the immune system. In particular, Tregs play a critical role in immune homeostasis by suppressing various aspects of the immune response. As a consequence of their role in coordinating the immune response, dysregulated Treg activity can lead to the development of various diseases and conditions. In particular, insufficient Treg function can result in autoimmune pathology, whereas excessive Treg activity has been linked to the inhibition of anti-tumour responses in cancer patients.
The protein GARP (Glycoprotein A Repetitions Predominant) has been identified as a highly expressed marker on the surface of Tregs, particularly activated Tregs. GARP is an 80 kDa transmembrane protein with an extracellular region comprising 20 leucine-rich repeats. It is also known as LRRC32. GARP serves as the receptor for TGF-β, particularly the latent form of TGF-β, and is required for the expression of latent TGF-β on Treg cells (E M Shevach. Expert Opin Ther Targets (2016) 21(2), 191-200).
TGF-β is a cytokine known to play a role in multiple processes including cell proliferation and differentiation, tissue morphogenesis, inflammation and apoptosis. It has also been identified as an important growth factor implicated in cancer development, and rather unusually, has been identified as a cytokine with tumour promoting and tumour suppressive properties.
The production and activation of TGF-β is a multi-step process, which is regulated at different levels. TGF-β is synthesised as a pro-TGF-β dimeric precursor, each polypeptide chain consisting of a latency-associated peptide (LAP) and a mature TGF-β region. Pro-TGF-β undergoes cleavage by the enzyme furin to form “latent TGF-β,” an inactive form in which the LAP remains non-covalently associated with the mature TGF-β region of each polypeptide chain (see FIG. 1). Membrane-localised GARP serves to transport and anchor latent TGF-β to the cell surface of Tregs, and it is from this membrane-bound GARP-latent TGF-β complex that the active form of TGF-β is released. A variety of mechanisms have been proposed to explain how active TGF-β is released from the GARP-latent TGF-β complex on the surface of Tregs. However, integrins, particularly αvβ6 and αvβ8, are now thought to play an important role in driving the shear forces needed for release of the mature TGF-β dimer.
Once released, the active TGF-β dimer can act as an autocrine or paracrine mediator of downstream signalling pathways. In the context of the immune system, TGF-β release from Treg cells is thought to influence the activity of various T effector cells and also Tregs themselves (see FIG. 1). Since Tregs play an important role in suppressing immunity, it is thought that TGF-β released from Tregs and acting in an autocrine fashion may be involved in mediating Treg suppression. In particular, Treg-derived TGF-β1 is thought to play a significant role in Treg-mediated suppression of tumour immunity.
Given the role of Treg-derived TGF-β in suppressing the immune response in the tumour microenvironment, there has been interest in targeting this pathway as an alternative approach to cancer immunotherapy. For example, therapeutic agents capable of dampening this pathway may serve as useful tools to improve the efficacy of cancer vaccines or other cancer immunotherapy strategies designed to harness the power of the body's immune system to treat cancer.
Cuende et al. (Sci Transl Med. 2015 Apr. 22; 7(284):284ra56) describes the production and characterisation of two monoclonal antibodies (MHG-8 and LHG10), which bind to the GARP-TGF-β complex on Tregs and inhibit TGF-β production. These two antibodies are also described and characterised in International patent applications WO2015/015003 and WO2016/125017. These antibodies were shown to be capable of inhibiting the immunosuppressive activity of human Treg in a xenogeneic graft-versus-host disease mouse model. This work serves to validate the GARP-TGF-β complex as a therapeutic target of interest for the purposes of modulating Treg function and consequently treating diseases such as cancer and autoimmune disease where the level of Treg activity plays an important role. There remains a need however, for improved GARP-TGF-β antibodies capable of inhibiting TGF-β release and thereby modifying Treg activity. The present invention addresses this problem as described herein.